Extra-articular diffuse-type tenosynovial giant cell tumor with benign histological features resulting in fatal pulmonary metastases

Abstract

Diffuse-type tenosynovial giant cell tumor (TS-GCT) is categorized as a locally aggressive but non-metastasizing neoplasm according to the WHO classification. Herein, we report an extremely rare case of a 41-year-old woman who developed multiple metastases from diffuse TS-GCT with benign histological features. The patient complained of a painful buttock mass and imaging studies revealed a soft tissue tumor of the buttock and multiple pulmonary nodules. The buttock tumor was excised and the final diagnosis was extra-articular diffuse-type TS-GCT. By video-assisted thoracic surgery, pulmonary nodules were pathologically identical to the primary tumor. Residual pulmonary nodules progressively grew, and she developed a muscle metastasis and a subcutis metastasis. She died of respiratory dysfunction due to multiple pulmonary metastases 1 year after primary surgery. Very few reports on histologically benign metastases from TS-GCT have been published, and the natural course of this rare condition remains unclarified. This rare case could provide important information for further clinical evaluation of this tumor.

Introduction

Tenosynovial giant cell tumor (TS-GCT) is a benign soft tissue tumor with histological features that include reactive inflammation and neoplastic proliferation. TS-GCTs are divided into four clinicopathological subtypes according to their growth pattern (localized or diffuse) and anatomical site (intra- or extra-articular). ¹ Localized TS-GCTs include intra-articular localized pigmented villonodular synovitis (PVNS) and giant cell tumor of tendon sheath and are usually treated by simple surgical excision. Diffuse types include conventional intra-articular PVNS and extra-articular diffuse TS-GCT and should be regarded as locally aggressive but non-metastasizing neoplasms. ² Development of metastases from histologically benign TS-GCT is extremely rare; to our knowledge, only five cases have been described in the English literature. ^{3 –7} Herein, we report a 41-year-old woman who developed fatal multiple pulmonary metastases from extra-articular diffuse TS-GCT without obvious histologically malignant findings. The patient was informed that data concerning her case would be submitted for publication, and she provided consent.

Case report

A 41-year-old Japanese woman had a 12-year history of a slowly growing mass in the right buttock and was referred to our hospital. Physical examination revealed a hard, elastic mass with pain exacerbated by digital pressure. Magnetic resonance imaging revealed a soft tissue tumor in the gluteus maximus muscle measuring 7 × 6 × 4 cm (Figure 1). A plain chest radiograph and computed tomography (CT) scans revealed multiple lung nodules highly suggestive of malignant disease, and fluorodeoxyglucose-positron emission tomography (FDG-PET) scans confirmed the buttock tumor and multiple lung nodules (Figure 2). A definitive pathological diagnosis could not be made by core needle biopsy. The differential diagnosis included giant cell tumor of soft tissue, sclerosing epithelioid fibrosarcoma, and undifferentiated/unclassified sarcoma. Pathological findings from an incisional biopsied specimen were identical to those of TS-GCT, without obvious sarcomatous transformation or any other type of histologically ominous evidence.

Figure 1.

Magnetic resonance imaging shows a soft tissue tumor in the gluteus maximus muscle. (a) T1-weighted image, (b) T2-weighted image, and (c) fat suppressed T1-weighted image with gadolinium enhancement.

Figure 2.

Plain chest radiograph (a) and FDG-PET scan (b) show multiple lung nodules.

Three weeks after the incisional biopsy, we performed a buttockectomy to completely remove the primary tumor. The patient was placed in lateral decubitus position and a curvilinear incision encompassing the biopsy site by 2–3cm was made. The incision began at the posterolateral aspect of the iliac crest extending distally passing over the greater trochanter and then curving posteriorly back along the gluteal skinfold. A fasciocutaneous flap was elevated and the sciatic nerve was identified distal to the resection site underneath the gluteus maximus muscle to determine resectability. The gluteus maximus muscle was mobilized from inferior and released from iliotibial band up to 5 cm proximal to the tumor. The inferior and superior gluteal vessels were ligated and the muscle was then dissected to its origin along the sacral alar and the sacrotuberous ligament. During surgery, general anesthesia was complemented by epidural anesthesia. Epidural analgesia was continued postoperatively and subsequently replaced oral analgesics. In order to prevent a postoperative seroma, for 72 h, a compressive dressing was applied and the patient remained supine position postoperatively.

Macroscopically, the tumor was located primarily in the gluteus maximus muscle and invaded the subcutis without association with the bursa or joint capsule (Figure 3). Histological examination of the excised tumor and surgical margin demonstrated microscopically complete resection (R0) in all directions. Pathological evaluation of the whole excised tumor revealed proliferation of mononuclear histiocytoid cells admixed with multinucleated osteoclast-like giant cells. The collagenous stroma was variably hyalinized, and focal metaplastic bone was apparent. The tumor microscopically infiltrated adjacent soft tissue structures; however, no areas of sarcomatous transformation were observed (Figure 4). The percentage of Ki-67-positive tumor cells was approximately 30%. The final diagnosis was histologically benign extra-articular diffuse-type TS-GCT. To confirm the pathology of the lung nodules, a pulmonary metastasectomy was performed by video-assisted thoracic surgery. The nodules were pathologically identical to the primary tumor. The patient chose best supportive care over palliative chemotherapy. Nine months after the buttockectomy, she complained of a painful nodule in her back and magnetic resonance imaging (MRI) revealed a metastatic tumor with a maximum diameter of 2 cm in the paravertebral muscle. Palliative radiotherapy (42 Gy/14 fractions) to the tumor reduced the back pain. Moreover, she developed a skin metastasis on the scalp.

Figure 3.

The tumor has no association with synovial tissues by a sagittal T2-weigted MRI (a) and a cut surface of the excised tumor (b). MRI: magnetic resonance imaging.

Figure 4.

Microscopy reveals proliferations of mononuclear cells without cellular atypia admixed with multinucleated giant cells (a). The tumor shows diffuse growth pattern to adjacent muscles (b). (hematoxylin and eosin stain, original magnification (a) ×200 and (b) ×50)

Following the sequential therapy in our hospital, palliative care was provided in another hospital. Progression of the lung metastases caused her respiratory symptoms and she required oral glucocorticoid therapy. One year after the primary tumor resection, she died of worsening respiratory status in a palliative care unit.

Discussion

Although TS-GCTs were initially regarded as an inflammatory reactive process, they are currently categorized as a “so-called fibrohistiocytic tumor” according to the WHO classification. ² TS-GCT is a benign tumor that usually originates from the synovium and tendon sheath; however, some cases develop without association with synovial tissues. Palmerini et al. ⁸ recently reported the largest series of TS-GCT, excluding only GCT of tendon sheath occurring in the hands and feet. Medical charts of 294 patients with TS-GCT were retrospectively reviewed; 69% of lesions were the diffuse type and 31% were localized. Local failure after surgery was higher among diffuse type compared to localized lesions (36% vs. 14%, p = 0.002); however, no metastases were reported. In the current WHO classification, diffuse-type TS-GCTs are regarded as locally aggressive but non-metastasizing neoplasms with uncertain behavior. ²

Although malignant TS-GCT is a very rare lesion, histological diagnostic criteria have been proposed. ^1,9,10 Some pathological experts have suggested that the designation of malignant TS-GCT should be reserved for lesions in which atypical-appearing benign TS-GCT coexists with frankly malignant areas, or when the original lesion is typical of a benign TS-GCT but the recurrence appears malignant. ¹ Bertoni et al. ⁹ reported eight cases of malignant TS-GCT and concluded that its important histological features were (1) a nodular, solid infiltrative pattern; (2) large, plump, round, or oval cells with deep eosinophilic cytoplasm and distinct borders; (3) large nuclei with prominent nucleoli; and (4) necrotic areas. In the present case, none of the histological features suggested malignancy.

The development of metastatic spread from a histologically benign, diffuse TS-GCT is extremely exceptional and as far as we know, only five cases have been previously reported in the English literature (Table 1). ^{3 –7} Metastases usually follow several local recurrences, with the duration from primary surgery ranging from 5 to 49 years. The present patient noticed a golf-ball-sized lump in the buttock 12 years prior to presentation, but she had not undergone any surgical treatment for the tumor. When she entered another hospital for surgery for a uterine myoma at the age of 35, no lung lesions were detected in routine preoperative examinations. Clinical outcomes were described in three of the five reported cases; one died of metastatic spread and two remained alive with disease. Asano et al. ⁶ speculated that these metastases from histologically benign lesions were an “implantation phenomenon” without potentially fatal malignancy and could be managed conservatively. In contrast, Sikaria et al. ⁵ reported a patient with histologically benign but clinically malignant metastatic TS-GCT. The patient was treated with molecularly targeted agents (an IGFR inhibitor, an mTOR inhibitor, and imatinib); however, he died of pulmonary metastases. The present patient did not choose systemic chemotherapy over best supportive care, and the pulmonary metastases worsened following this decision.

Table 1.

Reported case of histologically benign diffuse TS-GCT developing metastases.

Authors	Sex/age	Tumor location	Subtype	Metastases				Clinical outcome
				Site	Previous local recurrence (times)	Duration from primary surgery (years)	Treatment
Choong et al. 3	F/35	Popliteal fossa	Intra-articular	Soft tissue	5	49	NA	NA
Somerhausen and Fletcher 4	M/50	Popliteal fossa	Extra-articular	Lymph nodes	2	5	NA	NA
Sikaria et al. 5	M/49	Wrist and forearm	Extra-articular	Lung, lymph nodes	4	9	CT	DOD
Asano et al. 6	M/45	Proximal tibiofibular joint	Intra-articular	Lung, soft tissue, lymph nodes	1	8	None	AWD
Righi et al. 7	M/38	Knee joint	Intra-articular	Lymph nodes	3	25	CT	AWD
Osanai et al. (present case)	F/41	Buttock	Extra-articular	Lung, soft tissue, subcutis	0	0	RT	DOD

TS-GCT: tenosynovial giant cell tumor; CT: chemotherapy; RT: radiotherapy; NA: not available; DOD: died of disease; AWD: alive with disease.

The goal of management of diffuse-type TS-GCT is to remove the lesions as completely as possible while maintaining good limb function postoperatively. ¹¹ For recurrent or unresectable lesions, moderate-dose adjuvant radiotherapy might be able to provide good local control while maintaining good limb function. ¹² Recently, new agents for the treatment of relapsed TS-GCT have been proposed. TS-GCT commonly overexpresses colony-stimulating factor 1 (CSF1) resulting from a t(1;2) translocation. West et al. ¹³ reported that overexpression of CSF1 attracts non-neoplastic inflammatory cells that express CSF1 receptor (CSF1R). Imatinib is a multi-tyrosine kinase inhibitor that has activity against CSF1R. Imatinib became a promising candidate for treatment of relapsed TS-GCT after a case report of a recurrent TS-GCT that completely responded to imatinib. ¹⁴ Cassier et al. ¹⁵ reported the results of 29 cases of locally advanced and/or metastatic TS-GCT treated with imatinib. One patient experienced a complete response to imatinib, four patients had a partial response, and 20 patients had stable disease using version 1.0 of the Response Evaluation Criteria in Solid Tumors. These investigators reported that two patients with histologically malignant metastatic lesions rapidly progressed on imatinib and speculated that malignant TS-GCT might be less sensitive to CSF1R inhibition.

As shown by the case reported by Sikaria et al. ⁵ and the present case, histologically benign metastatic TS-GCT can be potentially fatal. Pulmonary metastatic spread in the present case was not promoted by surgical manipulation and must have been caused by an active multi-step process rather than passive implantation of tumor cells. We are not optimistic about this clinical condition. Our rare case report could provide important information for better understanding of the clinical behavior of histologically benign TS-GCT with metastases.